Trifluoroacetic acid → methyl 11-cyclohexyl-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxylate

HRID 1982923Notes

Reaction equation

HRID 1982923 reaction equation
C(O)(C(F)(F)F)=O.Br[C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[C:32]([CH:39]=[O:40])[CH:31]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.CC#N>[CH:18]1([C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:24]([O:26][CH3:27])=[O:25])=[CH:14][CH:15]=3)[N:10]3[CH:39]([OH:40])[C:32]4[C:33]([C:9]=23)=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=4)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1

Participants

10

Reactant 5

HCID 6422Trifluoroacetic acid2×HCID 10340Sodium CarbonateHCID 433294Lithium ChlorideHCID 27343652-Formyl-4-methoxybenzeneboronic acidHCID 11175076Methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate

Product 1

HCID 59682118methyl 11-cyclohexyl-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxylateYield 63%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 887MethanolSolvent2×HCID 6342AcetonitrileSolvent2×HCID 21863594Toluene ethanolSolvent

Conditions

Temperature
100 °C

Procedure

The general methods below were used with the following experimental procedures until indicated otherwise: LCMS data: Stop time: Gradient time+1 minute; Starting conc: 0% B unless otherwise noted; Eluent A: 5% CH3CN/95% H2O with 10 mM NH4OAc (for columns A and D); 10% MeOH/90% H2O with 0.1% TFA (for columns B and C); Eluent B: 95% CH3CN/5% H2O with 10 mM NH4OAc (for columns A and D); 90% MeOH/10% H2O with 0.1% TFA (for columns B and C); Column A: Phenomenex 10 4.6×50 mm C18; Column B: Phenomenex C18 10 3.0×50 mm; Column C: Phenomenex 4.6×50 mm C18 10μ; Column D: Phenomenex Lina C18 5μ 3.0×50 mm; Column E: Phenomenex 5μ 4.6×5.0 mm C18. To a slurried solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (4.3 g, 13 mmol), 4-methoxy-2-formylphenylboronic acid (3.0 g, 17 mmol) and LiCl (2.2 g, 51 mmol) in EtOH/toluene (1:1, 100 mL) was added Pd(PPh3)4 (1.4 g, 1.3 mmol) and then 1M Na2CO3 (aq.) (32 mL, 32 mmol). The reaction solution was flushed with nitrogen and heated at 100° C. for 3 h and cooled to rt. The reaction was concentrated to remove EtOH, diluted with H2O (200 mL) and extracted with EtOAc (2×150 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated to dryness. The residue was triturated with CH2Cl2 and the solids were collected by filtrated and washed with Et2O and CH2Cl2 to yield methyl 11-cyclohexyl-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxylate (3.0 g, 8.0 mmol, 63%) as a yellow solid which was used without further purification. LCMS: m/e 374 (M+H)+, ret time 3.09 min, column B, 3 minute gradient.

Workup

  1. customGradient time+1 minute
  2. customThe reaction solution was flushed with nitrogen
  3. temperaturecooled to rt
  4. concentrationThe reaction was concentrated
  5. customto remove EtOH
  6. additiondiluted with H2O (200 mL)
  7. extractionextracted with EtOAc (2×150 mL)
  8. washThe combined organics were washed with brine (100 mL)
  9. dry with materialdried (MgSO4)
  10. filtrationfiltered
  11. concentrationconcentrated to dryness
  12. customThe residue was triturated with CH2Cl2
  13. customthe solids were collected
  14. filtrationby filtrated
  15. washwashed with Et2O and CH2Cl2

Sources & evidence

ORD record
ord-9ca74e39d7c944c39b2cbfdfb77181a5
Source dataset
uspto-grants-2009_06
Patent number
US07541351B2

Reaction notes

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